DE1470074A1 - Hexahydro-11bH-benzo [a] quinolizines and processes for their preparation - Google Patents

Description

U70074

E. M e r c k February 12, 1969 Ak tiongefio 11 switch

Darmstadt

Hexahydro-1 IbH-benzo / Vquinolizine and processes for their manufacture

The invention relates to hexahydro-HbH-benzo / qjchinolizine of the general formula I.

wherein

R is a methyl, ethyl, ethynyl or phenyl group,

R is hydrogen or a methyl group and

R is hydrogen or a chlorine atom χ,

as well as their esters and acid addition salts.

The new hexahydro-HbH-benzo / * a7chinolizine have very valuable pharmacological properties. Above all, they show anesthesia-potent, also depressive, e.g. tranquillizing and neuroleptic and / or thymoleptic as well as effects on the circulatory system

The invention relates to hexahydro-HbB-benzo / q / quinolizines of the general formula I, their esters and acid addition salts and a process for their production which consists in that one a ketone of the general formula II

BAD ORiGiNAL 9098A1 / 1696

U7007A

wherein

R and R have the meaning given to have

II

in ε η a well-known way with an organometallic compound of the general formula III

R-II wherein

R has the meaning given, M is an alkali metal, preferably

Lithium atom or the group -MgX

and

X represent a chlorine, bromine or iodine atom,

reacted in an organic solvent and optionally a compound of the formula I in which the radical R is an ethynyl group, catalytically hydrogenated and / or optionally the compound obtained by treatment with acylating agents into their physiologically acceptable esters and / or by treatment with acids in their physiologically compatible acid addition ■ salse converts.

In detail, as ketones of the formula II, the unsubstituted _and 2-oxo-1 ₁ 2,3,4,6,7-hexahydro-HbB-benzo / Vquinolizine and 9-Ctalor ^ 10-Methy l-2-oxo-l, 2,3,4, eyT-hexahydro-IIbH-benzo / vquinolisine preferred. Some of the ketones of the formula II are known and can be obtained, for example, by the methods given in the following literature references: Chemischeberichte, Volume 95, page 2132 (1962); German Auslegeschrlft 1 134 678 and German Auslegeschrift 1 068 261.

• 0M41 / 1 ·! ·

U70074

Organometallic compound of the formula III can be an organoalkali metal, preferably an organolithium compound or a Grignard compound of the formula R-MgX can be used.

The reaction of the ketone of formula II with the organometallic compound of formula III is preferably carried out in the fUr such reactions common solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, anisole, benzene, toluene, Xylene or other hydrocarbons or mixtures of these solvents.

Either the ketone of the formula II or a solution of this ketone can be used to form a solution of the organometallic compound add or, conversely, add a solution of the organometallic compound to a solution of the ketone. The reaction temperature is not critical and can be between -10 ° and the boiling point of the respective solvent. It is preferred to work with cooling at the beginning, and in some cases in the usual way, see B. by addition a little iodine, which initiates the reaction. To get the reaction sum To bring it to a close, it is usually stirred for a while, left to stand or heated for a shorter period of time. Working up is carried out in the customary manner by adding Water, salt solutions (e.g. ammonium chloride solution) or acids and extraction with organic solvents.

In some cases, especially when reacted with unsaturated organometallic compounds, essentially arises

ORIG | _NAL

90M41 / 16M

H70074

a single reaction product. In other cases, on the other hand, two diastereomeric racemates are obtained, which are optionally can be separated by fractional crystallization and / or chromatographic methods. • If desired, it is also possible to obtain a racemate in the usual way in the optically active antipodes disassemble; this can be done, for example, by a salt of such a racemate with an optically active Acid fractionally crystallized. Dibenzoyl-D-tartaric acid and D-camphor sulf are, for example, optically active acids onic acid or D-tartaric acid into consideration. Optically active End products are also available using an optically active ketone II as the starting material.

Such compounds of the formula I in which the radical R represents an ethynyl group can be hydrogenated to the corresponding ethyl compounds, line such Hydrogenation takes place in a manner known per se catalytically, where the catalyst is preferably ideal metal catalysts used. These can be used as supported catalysts, such as palladium on cabbage, calcium carbonate or Strontium carbonate, ai8 oxide catalysts wi · jb.B. Platinum oxide, or in the form of finely divided metal catalysts · di · hydrogenation

I0M41 / 1S ··

.-δ- Η70074

can be carried out at home and at normal pressure or at elevated temperature and / or elevated pressure. · Preference "weiue arboitet men look at pressures zv / i 1 and 100 at and Temperuturon between Rauintenperatur and + 150 ⁰ C. Suitable solvents for the hydrogenation are especially methanol, ethanol, isopropanol, tert-butanol, ethyl acetate, Dloxan, glacial acetic acid , Tetrahydrofuran is suitable. In some cases we recommend the addition of catalytic or equimolar amounts of mineral acid, for example salt or sulfuric acid. Instead of the free Uaββ, a salt of the base can also be used. During the hydrogenation care must be taken that the aromatic king is not also attacked. It is therefore preferable to operate at normal pressure in such a way that m & n stops the hydrogenation after the calculated amount of hydrogen has been taken up.

A compound of the obtained by the process of the invention Formula I can be added to your by treatment with aoylating agents physiologically compatible esters are converted. As an aoylating agent are all those acids bsw. Their dorivate suitable for esterification can be used, the physiologically compatible Esters result. For example, the following acids or their derivatives suitable for esterification can be used: Carboxylic acids such as Acetic acid, propionic acid, butyric acid, yalanic acid, isovierlanic acid, Trimethyl acetic acid, caproic acid, oenanthic acid, caprylic acid, Palmitic acid, undecylenic acid, benzoic acid, uexahydrobenoic acid, Cyclopentyl, cyclohexyl or aryleasig and propionic acids such as Phenylesslg- or phenylpropionic acid, as well as Halogencarbonstlurea like Chloresslgsuure, AothersUuren or beterooyollache acids like Furanoarboxylic acid (2) or nicotinstture. If necessary, maa also for the production of water-soluble derivatives bit dicarboxylic acids, amino or alkylaminocarboxylic acids or old phosphoric or sulfuric acid to esterify. In this way, see B. Oxalates, suoolnates, maleates or the acid addition salts of aainooarboxylic acid esters, such as, for example, aspartic acid or diethyla-binoacetic acid esters. Derivatives suitable for esterification are also the free ones Acids, for example, their halide, anhydride, and thlol derivatives as well as ketenes. F) Mr Umestertngsmetaodea are also lower alkyl esters

BAOORlGiNAL

A pre-binding of the formula I obtained by the method of the invention can also be converted into the associated acid addition salt in the usual way with an acid. I ¹ Ur this implementation are those acids that produce physiologically harmless salts. Organic and inorganic acids, such as x. B. aliphatiocho, alioyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, pivalic acid, diethyloslgic acid, oxalic acid, malonic acid, succinic acid, picolinic acid, fumaric acid, maleic acid, amino acid , Sulfamine acid, benzoic acid, salicylic acid, phenylproplous urine, citric acid, gluconic acid, ascorbic acid, isonicotinic acid, hethanesulfonic acid, ethanedisulfoic acid, U-hydroxyethanesulfonic acid, p-toluenesulfonic acid, naphthalic acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid , or phosphoric acids, such as ortho-

phosphoric acid can be used.

The new compounds can la mixture of old conventional drug carriers be used in human or veterinary medicine. The carrier substances used are organic or inorganic Substances in question that are suitable for parenteral, enteral or topical application and those with the new compounds are not react, such as water, vegetable oils, Polyethylene glycols, gelatine, lactose, starch, magnesium aastearate, Talc, petroleum jelly, cholesterol. Solutions, preferably thin or aqueous solutions, are used in particular for parenteral administration Solutions, as well as suspensions, anilions or implants. Tablets or are also suitable for enteral administration Dragees, for topical application ointments or creams »the if necessary, sterilized or old auxiliary materials, such as preservatives, Stabilizing or wetting agents or salts to influence the osmotic pressure or old buffer substances are offset.

The substances according to the invention are preferably in one Dosage from 1 to ICO ag applied per dosage unit.

U7007 *

example 1

To a solution of mothyllithium under dry nitrogen, which was prepared from 14.3 g of methylbroniide and 2.1 β of lithium in 200 tal of absolute ether, a solution of 20.1 β 2-0X6- is added at -10 ° urtter stirring. 1,2,3,4,6,7-hexahydro-libII-benzo / a / chlnolizine in 100 el of absolute tetrahydrofuran. Then allows the reaction mixture to rise to room temperature and stirs for about 15 hours. Thereafter it is acidified with hydrochloric acid, the ether-tetrahydrofuran mixture is separated off, the aqueous phase is alkaline with sodium hydroxide and extracted with ether. The ethereal extract is dried over Uagnosiunsulf & t and evaporated. The residue - 18.9 g of oily 2-hydroxy-2-ethyl-1,2,3,4,6,7-hexahydro-llbli-bcnzo / a / chlnolizln - lust nan in 100 ml of boiling cyclohexane. After standing for a long time at the tinplate temperature, 10.4 g of the less soluble racenate with a temperature of 194 ° can be sucked off. The mother liquor is evaporated and the residue is chromatographed on a silica gel-filled column. With a Gonisoh made of benzene and triethylamine (8: 2), nan first elutes the easily soluble

Racenate, which scales at 104 °. It is nit drone in Aether is converted into the hydrobronide, which according to Uncrystallisleren from alcohol / ether melts at 180 - 187 °; the exploit is 7 g. Washing out the silica gel column with methanol gives another 1.4 g of the racemate with a temperature of 134 °, its hydrobronide melts after uncrietullizing from alcohol / ether at 205-300 °.

Example 2

Prepare from 2.1 g of lithium and 16.4 g of Aothylbronid in 100 ml absolute aother under nitrogen an Aethyllituiuu-LUsunij and alliaahlich gives a solution of 20.1 g of 2-oxo-1,2,3,4,0,7-hexaIydrollbll-benzo / a / quinolzine in 150 nl absolute aother under RUhron to. Then stir for 30 minutes at room temperature and then boil another 2 hours under RUokfluO. You add water, add saIaic acid on, separates the aether and shakes it nooh awoimal old dilute hydrochloric acid and the like. The combined hydrochloric acids Aua / Ugo become clarified with activated charcoal, old caustic soda alkaline waxed and

909841/1696 _BAD

U70074

-β -

ether. The ether extract is dried over magnesium sulfate and steams him up. The remaining racemate mixture of 2-Ethy1-S-hydroxy-1 ^ .S ^ fe ^ -hexahydro-llbH-benzo / VchlnollzlnB is dissolved in 300 "1 acetone and acidified with ethanolic hydrochloric acid. After standing for 1 to 2 days, 7.3 g of the hydrochloride crystallize less soluble racemates with a melting point of 224 °. The mother liquor is evaporated and the residue with ether and diluted Caustic soda added. The ethereal solution is dried briefly over magnesium sulphate and then with ethereal hydrobromic acid acidified. After the hydrobromide has deposited, the ether is decanted off and the precipitate is triturated with 200 ml Acetone. The hydrobromide is filtered off with suction and recrystallized from isopropanol. 7.2 g of hydrobromide of the more readily soluble racemate with a melting point of 2o2 ° are obtained. The corresponding hydrogen malonate melts at 158 ° (from ethanol).

Example 3

To a / · under nitrogen Phonyl-Lithiunlüsung, the nan from 2.1 g of lithium and 23.5 g of bromobenzene in 200 μl of absolute ether has prepared, dripping nan under ItlUiren at low temperature is running one hour of a solution of 20.1 g of 2-0xo-1,2,3,4,0,7-hexahydrollbll-benzo / a / chiuolizine in 100 ml of absolute tetrahydrofuran. After standing overnight, nan uit dilute hydrochloric acid acidifies, separates the ether / tetrahydrofuran mixture from, maoht the aqueous phase ■ lt caustic soda alkaline and extracted with ether. The United Ether extracts are dried over magnesium sulphate and evaporated. The fragmentary chromatography is performed on a silica gel column. Initially, a benzene / triethylamine mixture is used as the solvent. The host of the sparingly soluble isomer becomes with methanol ausor / asohen. The two isomeric racenates of 2-hydroxy-2-phenyl-1,2,3,4,6, T-hexchydro-IIIiH-bonzo / a / quinolizine have been transferred to the hydrochloride, of which it is easier to dissolve after recrystallization from ethanol / ether melts at 224 °. (Yield 3.9 s). Da3 HyrtrobromiU of the ochworer soluble Racouateu is made from laopropanol uuUristallioioi-t. Γ. 504 °. Yield 14.4g.

909841/1696 bad original

H7007A

Example 4

To a solution of ethynyl magnesium bromide in tetrahydrofuran a solution of 20.1 g of 2-0 :: o-l, 2,3,4,6,7-he :: ahydro-.llbH-benzo / * a7quinolizine is added with stirring within about 30 minutes in 100 ml of absolute tetrahydrofuran. After standing for two days at room temperature, it is decomposed with dilute hydrochloric acid and distilled the tetrahydrofuran in a vacuum and ether out once. The acidic aqueous phase is now made alkaline with sodium hydroxide solution and with Aether extracted. The residue obtained after drying and distilling off the ether contains practically only one of the two possible racemates. It is precipitated as a hydrobromide and made from isopropanol uracrystallized. 13.2 g of 2-A-thiny1-2-hydroxy-1,2,3,4,6,7-hexahydro-IIbH-bcnzojTa / quinolizine hydrobromide are obtained from the F. 227 °. 3 g of the Hydrobroraids are in 100 al of methanol in the presence of Pd-carbon catalyst hydrogenated. After recording the calculated Amount of hydrogen, the hydrogenation comes to a standstill, and one obtains after distilling off the methanol and recrystallization from Ieopropanol, 2.7 g of 2-ethyl-2-hydroxy-1,2,3,4,6,7-hexahydro-HbH-benzo ^ "a / quinolizine-hydrobroraid from F. 2o6 - 207 °.

Example 5

2 g of 2-hydro: ry-2-ethyl-1, 2,3,4,6,7-hexahydro-IIbH-benzo / "a / chlnolizln (low-melting racemate, F. 202) are altogether 1 g dry fine Powdered sodium acetate and 25 μl acetic anhydride are heated for 12 hours with stirring in a nitrogen atmosphere to 120 °. The reaction mixture is then evaporated to dryness in vacuo, the residue is taken up in dilute hydrochloric acid with cooling and the product is extracted as ether. The ether layer is dried using sodium sulfate and concentrated, whereby d & s 2-acetoxy-2-ethyl-1,2,3,4 _t e, 7-hexahydro-llbH-benzo / quinolizine crystallizes "

The acetate obtained can with hydrogen chloride in methanol / ether in his Hydrochloric! To be convicted.

t9M41 / 1IM

Example 6

Acetylene is introduced into a solution of 15.3 g of lithium in 500 ml of liquid ammonia, initially cooled to -40 °, until the previously deep blue solution has become discolored. Without removing the cooling, 224 g of 10-methyl-2-oxo-1,2,3,4,6,7-hexahydro-IIbH-benzo / a / ^r quinolizine, dissolved in 800 ml of absolute tetrahydrofuran, are now added dropwise with stirring to. The mixture is then stirred for a further 5 hours at -40 °, the cooling is then removed so that the ammonia evaporates, and water is carefully added. The tetrahydrofuran solution is separated off and, after drying over magnesium sulfate, evaporated. The evaporation residue is dissolved in 2.5 liters of methanol and, after the addition of 50 g of palladium-carbon, hydrogenated to a standstill at normal pressure and room temperature. After the catalyst has been filtered off with suction, the methanol is distilled off and the practically pure, sparingly soluble racemate of 2-ethy 1-2-hydroxy-10-methyl-1,2,3,4,6,7-hexahydro-HbH-benzo is obtained ^ ä / -quinolizins from F. 136. The base is precipitated as a hydrobromide from an ethereal solution. After recrystallization from ethanol, the hydrobromide, which is uniform according to thin-layer chromatography, melts at 205 °. The yield is 210 g. The base obtained and its salts show a good antihypertensive effect «

Representation of the output connection:

332 g of 7-methyl-3,4-dihydroisoquinoline hydrochloride vom

F. 178-179 ° are increased in portions to 335 g with stirring added heated methyl vinyl ketone to the steam bath. When the addition is complete, the mixture is stirred on the steam bath for a further 1 hour.

It is allowed to cool, 700 ml of acetone are added and the hydro-

chloride des 10-methyl-2-oxo-1 _t 2,3,4,6,7-hexahydro-llbB-benzo ^ "a / quinolizins from. Mp. 208 °.

The Hydrochloric! is marked with Χ »!» lye into the free base (F. 95 97 °) ttberfoftthrt.

U70074

A solution of 43 g of 10-methyl-2-oxo-1,2,3,4,6,7-hexahydro-1 is slowly added to a solution of ethynyl magnesium bromide at room temperature with stirring IbII-benzo / Vquinolizine in 200 ml absolute Given tetrahydrofuran. The mixture is stirred for 3 hours at room temperature and 1 hour at 40 ° and then decomposed by careful Addition of dilute hydrochloric acid. The hydrochloric acid aqueous solution is washed with ether, made alkaline by adding ammonia and extracted with ether. The one after drying and evaporation The residue remaining from the ether extract is hydrogenated as in Example 9. 39.5 g of 2-ethyl-2- hydroxy-10-methyl-1,2,3,4,6 are obtained 7-hexahydro-HbH-benzo / * a7quinolizine hydrobromide as a uniform Racemate with a temperature of 205 °.

Example 8

Analogously to Example 2, 10-methyl-2-oxo-1,2,3,4,6,7-hexahydro-HbH-henzo / ~ a7quinolizine is obtained and ethyllithium, the two racemates of 2-ethyl-2-hydroxy-10-methyl-1,2,3,4,6,7-hexahydro-IIbH-benzo ZVchinolizins with a temperature of 136 ° (hydrobromide, temperature 205 °, from ethanol) or b.p. 145 - 147 ° / O, 0.5 mm (Hydrobroraid, temperature 173 - 174 °).

Example 9

To one made from 4.43 g of lithium and 38.3 g of ethyl bromide Ethyl lithium solution in absolute ether is added 42 g of 9-chloro-2-0X0-1,2,3,4,6,7-hexahydro-llbB-benxo ^ Vquinolizine, dissolved la a mixture of absolute ether and tetrahydrofuran. To 3 hours of boiling under nitrogen, it is decomposed with water, isolated the organic phase, dry and evaporate. The raw base is chromatographed on silica gel with benzene / triethylamine (9: 1), From the more easily soluble racemate of 9-chloro-2-ethyl-2-hydroxyl, 2,3,4,6,7-hexahydro-IIbH-benzoA7-quinolizine 12.7 g of a hydrobromide with a melting point of 210 ° are obtained from the less soluble racemate 15.1 g of a hydrobromide with a melting point of 220 °.

BATH

90S841 / 169S

Establishing the output connection:

3-chloro-N-formyl-ö-phenylät hy larain, obtained by reduction of 3-chlorobenzyl cyanide with lithiuraaluminiurahydride / aluminum chloride and subsequent formylation, is converted into e-chloro-S ^ -dihydro-isoquinoline by heating it with polyphosphoric acid cyclislert. Use a small amount of the 8-chloro-3,4-dlhydro-isoquinolene formed next to it can be removed by recrystallizing the hydrochloride from ethanol. The 6-chloro-3,4-dihydroisoquinole hydrochloride (M.p. 222 °) is, as described in Example 6, condensed with methyl vinyl ketone, 9-chloro-2-ox »-l, 2,3,4,6,7-hexahydro-llbH-benzo / 'a / -quinolizine hydrochloride received from the F. 210 °.

Example 10

line solution of 7.4 g of potassium in 185 ml of tert-butanol is mixed at room temperature with a solution of 9.3 g of 2-oxo-10-methy1-l, 2,3,4,6,7-hexahydro-IIbH- benzo4f% 7c ^nln ° H- ^z ^ ^{n un} <* 135 ml of tert-butanol added. Now pure nitrogen is passed through the mixture for about 15 minutes and then a weak stream of acetylene. After about 4 hours, the tert-butanol is distilled off, the oily residue is taken up in water and shaken out several times with ether. The combined flour extracts are dried over magnesium sulfate and evaporated, the 2-hydroxy-2-ethinyl-10-methyl-1,2,3,4,6,7-hexahydro-HbH-benzo / V quinolizine obtained is distilled at 145 ° / O , O5 mm. Hydrobromide, m.p. 253 °; Yield 4.5g. Only one of the possible racemates is obtained.

BATH ORIGINAL

909841/1696

U70074

The valuable pharmacological ones are shown in detail Properties of the process products in the comparison tests listed below.

1, anesthetic potentiating effect.

The anesthesia-potentiating effect was determined in the hexobarbital anesthesia test determined at Ratton. In this test, 10 females each receive Rats (weight 130-230 g) after 20 hours of food deprivation graduated amounts of the test substances (in gum arabic solution suspended) administered orally. A group of 10 control animals receives a 5% gumra arabicum solution orally at the same time. 45 minutes thereafter, all animals are given intravenous hexobarbital sodium (20 mg / kg) administered. The animals lie on their back heated tubs. The duration of anesthesia for the animals is determined on the basis of two criteria (lifting of the head and again positive reverse reflex) and compared with each other. As the minimum effective dose of the test substances the lowest dose is defined at which there is a clear difference in effect compared to the control animals (statistical verification with Liann-Whitney test).

Compared to the ice cream product ueprobamate (2-methyl-2-n-propyl-1,3-propanediol-dlcarbamate) The following relationships resulted from the minimally effective doses, the toxicity levels (LD 50) and the therapeutic indices:

9098 * 1/16 * 96 bad original

Investigated connection anesthesia-
potential—
round
effect toxicity
(LD 50) therapeu
table
index Meprobamat (compar
substance) 1 1 1 1,2-, 3,4,6,7- hexahydro-
llbH-benzo ^ ~ a / quinoli-
interest (each easier
soluble raceroate): 2-hydroxy-2-ethyl 10 0.7 7th 2-hydroxy-2-methy1- 4th 0.9 3, β 2-hydroxy-2-ethyl
9-chlorine- 20th > 0.13 2-hydroxy-2-ethi-
nyl- 1) 3 0.95 ι. » 2-hydroxy-2-ethyI-10-
methyl- 3 0.53 Ι, β 2-acetoxy-2-ethyl 4th > 0.37 > 1, β 2-hydroxy-2-phenyl- 1." > 0.8 > 1.2

1) only get a Raceraat «

It can be seen that the process products in up to 2O-fold A lower dose have the same strong effect as the comparative preparation, and that their therapeutic indices are higher are than that of the comparative preparation.

• 09141/169 *

2. Effect on the circulatory system

The process products
C - a

benzo / quinolizine (as hydrobromide; less soluble of the two possible racemates)

D - 2-Hydroxy-2-ethinyl-10 ~ methyl-1,2,3,4,6,7-hexahydro-llbB-benzo / a / quinolizine (as hydrobromide)

show a specific effect on blood circulation, which is particularly evident in an increase in the volume of blood flow peripheral Arteries and is fundamentally different from the e.g. the well-known commercial preparation xanthinol niacinate (X; 7- / Z-hydroxy-3- (N-2-hydroxyethyl-N-methyl-amino) -propylZ-theophylline nicotinate).

For example, in anesthetized dogs in Doeierur from 0.005 mg / kg (intravenous), C led to a strong, long-lasting effect. Increase in the volume of current in the periphery (femoral artery, vertebral artery; measured with the electromagnetic flow meter from Uedicon 11-4001); with higher doses the effect increased in intensity and duration. At even higher doses (from 1 mg / kg) the blood pressure fell. In conscious dogs, doses of 0.02 to 0.5 mg / kg increased muscle blood flow without affecting skin blood flow or blood pressure Su

Process product D showed an increase in the flow volume of the femoral artery after 0.5 mg / kg in anesthetized bandages. of 50 - 100% and 10 to 20 minutes duration Doses of 2 and 0 mg / kg lead to an increase of over 100% in the current volttaea of over 40 minutes. So she got the Dosl-bhlagigkoit especially in the increase in the duration of action.

BATH

101141/1 (91

By comparison, the known compound X was anesthetized and wakeful dogs 10 to 20 times less potent than Compound C; for example, compound X only worked at a dose of 10 mg / l a comparable, i.e. over 100% increase in the current volume which, however, was of short duration (1-3 minutes) · The products of the process thus produced in doses that Orders of magnitude below the corresponding doses of the comparator preparation, a stronger and longer lasting one Increase in flow volume of peripheral arteries

Dosages of 2 and 5 mg / kg of compound D caused anesthetized dogs had a 5-10% increase in cardiac output that lasted for 30-40 minutes. In contrast the comparison substance X showed an opposite effect, i.e. X led in a dose of 10 mg / kg to about 10% decrease in cardiac output

Taking into account the toxicities, the results were as follows Effect relationships:

effect
(Increase in
81 room volume) toxicity
(LD 5Q) Therapeu
table
index Examined
link 1 1 1 X (compar
substance) 20th
10 * ο. β
> a IS
> ao C.
D.

It can be seen that the product of the process differs from the comparison not only because of the action mechanism, but both by their greater effectiveness as well as by their better ones different therapeutic index. rad ORIGINAL

• OS * 1/1698

H70074

Further comparative studies between the process product C and the Ilandelspraparat nylidrin hydrochloride (N) were Carried out on anesthetized cats and dogs, on conscious dogs as well as on the vascular system of the isolated rabbit rabbit.

The blood pressure measurements in anesthetized cats and dogs were carried out with Statharo pressure transducers on the femoral or brachial artery. The changes in current volume were measured with the electromagnetic flow meter (Ifedicon 4000). On conscious dogs, blood pressure and peripheral blood flow were measured using the SCHROSDER test arrangement ( Archive for Circulatory Research, Dand 15, page 24 (1949); Zeitschrift für experimental Medizin, Volume 117, page 181 (1951); ibid., Volume 130, Page 513 (1959).

These tests showed the following results:

1. On anesthetized dogs and cats, compound C and nylidrin-hydrox'ochloride had practically the same strength in the same dosage dilating. In doing so, however, compound C showed a lesser (undesired) antihypertensive effect and a significant one lower (undesired) increase in pulse rate than the comparison substance N in equally strong vasodilating doses. Taking into account the toxicity, nax * kotlslerten were found Dogs the following effects:

dose
(mg / kg) Examined
link vasodi-
latleren-
de effect Toxlzi-
tttt
(LD 50) Thera
peut 1-
echer
index blood
pressure
waste Elevation
the pulse
frequency BATH ORIGINAL 0.01 N (ver
equal
substance)
C. 1
approx 1
1.4 1
about 1.4 20%
8th % 90%
10% 0.02 N ( ver
equal
substance)
C. 1
approx 1
•
1.4 1
approx. l, 4 24%
15% 35%
10%
« 909841 / 1896

It can be seen that the product of the process is approximately equal in strength, ker vasodilating effect a lower toxicity (higher · LD 50) and therefore a better therapeutic index than the Has reference substance; when the product is administered, the blood pressure drops only about half as much, and the increase in pulse rate is only one third of the increase caused by the reference substance.

2. In v / achen dogs , compound C caused a distinct and long-lasting increased blood flow in the muscle vessels, while the blood flow in the skin vessels was reduced. A decrease in blood pressure was not observed. The comparison substance N always led to an increase in both muscle and skin blood flow and to a significant decrease in blood pressure.

3. In the isolated rabbit ear, compound C led to a concentration-dependent increase in perfusion of 30-300%. The comparator preparation N, on the other hand, had a clear vasoconstrictor effect; a vasodilating effect only occurred after prior application of a substance with a renolytic effect (phentolamine).

In summary, it is found that the process product C, in contrast to the commercial preparation N, a significant increase in Causes blood flow to the skeletal muscles without impairing blood pressure. The hand preparation resulted in the same Experimental arrangement for the decrease of the peripheral resistance with a drop in blood pressure.

The increase in blood flow, especially in the area of the skeletal muscles, if there is no (or only slight) simultaneous impairment of blood pressure and pulse rate significant advantages of the process product compared to the commercial product.

909841/169 «

Claims (10)

Patent claims: 1. 1,2,3,4,6,7-Hexahydro-HbH-benzo / a / quinolizine of the general Formula I. wherein R «ine methyl, ethyl, ethynyl or pnenyl group, R is hydrogen or a methyl group LJ and ^{R 0H} R ² hydrogen or a chlorate » I mean as well as their esters and acid addition salts, 2. 2-Hydroxy-2-methyl-1,2,3,4,6,7-hexahydr6-llbH-benzo / 7quinolzln. 3.2 ~ Hydroxy-2-ethyl-1,2,3,4,6,7-hexahydro-IIbH-benzo / V '^ izin. 4. 2-Acetoxy-2-ethyl-1,2,3,4,6,7-hexahydro-llbH-benzo / V ^c ^ ^ia olizin · 5. 2-Hydroxy-2-ethinyl-1,2,3,4,6,7-hexahydro-IIbH-benzo / ~ a / quinolzlr 6. 2-Hydroxy-2- ethy 1-9- chloro-1,2,3,4,6,7- hexahydro- HbH-benzo / V chi- nollzlc 7. 2-Hydroxy-2-ttthyl-10-methyl-1,2,3,4,6,7-hexahydro-llbH-DeMoA7- ohinollzin. 8. 2-Hydroxy-2- äthiny 1- 1O-methyl-1,2,3,4,6,7-hexahydro- HbB- benzo / Vchlnolizln. 9. 2-Hydroxy-2-phenyl-1,2,3,4,6,7-hexahydro-HbH-benaQ / Vehlnollmln. 909041/16 $ -2Q- 10. Process for the preparation of 1,2,3, 4 , 6,7-hexahydro-IIbH-bcnzo / * a / quinolizines of the general formula I. wherein R is a methyl, ethyl, ethynyl or phenyl group, . , ^ y, ■ _> ^ ₁ ^ _w R hydrogen or a methyl group R I ^ I pe and
ο
R is hydrogen or a chlorine atom mean, and their esters and acid addition salts, characterized in that a ketone of the general formula II wherein R and VC have the meaning given II ° in a manner known per se with an organometallic compound of the general formula III ' wherein R has the meaning given, R-M If an alkali metal, preferably St. Lithium atom or the group -MgX and
X. a chlorine, bromine or iodine atom mean, Reacts in an organic solvent and optionally a Compound of the formula I in which the radical R denotes an ethynyl group, catalytically hydrogenated and / or optionally the one obtained Compound by treating with acylating agents in their physiological compatible esters and / or aurcn treatment with acids into their physiologically compatible acid addition salts. 909841/1696 bad original